Trans-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Abstract

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p<5×10-8) with GDM, mapping to/near MTNR1B (p=4.3×10-54), TCF7L2 (p=4.0×10-16), CDKAL1 (p=1.6×10-14), CDKN2A-CDKN2B (p=4.1×10-9) and HKDC1 (p=2.9×10-8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

The Genetic Risk of Gestational Diabetes in South Asian women

“…Consistent with a recent trans-ethnicity GWAS of GDM, and these results support the hypothesis that GDM and type 2 diabetes are part of the same underlying pathology. (Pervjakova et al, 2021)…”

“…MTNR1B) might have significantly different effect size depending on the phenotype studied. (Pervjakova et al, 2021) In addition, variants in at least one locus ( HKDC1) have been strongly associated to GDM but not type 2 diabetes. (Pervjakova et al, 2021) More GDM-specific loci, or loci with a different magnitude of effect between GDM and type 2 diabetes might be identified from future, larger studies.…”

“…(Pervjakova et al, 2021) In addition, variants in at least one locus ( HKDC1) have been strongly associated to GDM but not type 2 diabetes. (Pervjakova et al, 2021) More GDM-specific loci, or loci with a different magnitude of effect between GDM and type 2 diabetes might be identified from future, larger studies. These observations suggest that future PRSs based on a GDM GWAS may have a higher predictive value and more power to detect gene×environment interactions.…”

“…(Vounzoulaki et al, 2020) In terms of genetic architecture, both candidate gene and genome-wide association studies (GWASs) demonstrated a considerable overlap between GDM and type 2 diabetes. (Hayes et al, 2013; Kwak et al, 2012; Pervjakova et al, 2021) Finally, type 2 diabetes polygenic risk scores (PRSs) have also been associated with GDM risk. (Lamri et al, 2020; Pervjakova et al, 2021)…”

“…(Hayes et al, 2013; Kwak et al, 2012; Pervjakova et al, 2021) Finally, type 2 diabetes polygenic risk scores (PRSs) have also been associated with GDM risk. (Lamri et al, 2020; Pervjakova et al, 2021)…”